The opiate mu receptor site will be mapped using accurate high- resolution x-ray measurements at low temperature of the electron density distributions and molecular electrostatic potentials of a series of opiates and related molecules. Since x- rays are scattered by electrons in a molecule it is possible using accurate x-ray diffraction measurements of single-crystals to obtain an experimental three-dimensional map of the electron distribution. And since x-rays also provide a detailed description of the shape of a molecule, both the stereochemical and electronic factors which determine the strength of drug-receptor interactions may be obtained from the same experiments. Drugs of the opiate class are among the most highly studied by both experimental and theoretical methods, and remain of widespread medical use both as potent analgesics and as antagonists in the treatment of overdoses. Modern methods of molecular drug design offer the promise of discovering many new drugs if the details of the drug-receptor interaction are understood. The opiate receptor, however, has not been structurally characterized. The methodology of this project will be to use the structures and experimental electron distributions measured on a series of opiate drugs to build a three-dimensional model of the receptor by assuming it is complementary both in shape and charge distribution to active drug molecules. Specific drug molecules to be studied include rigid opiates such as nalorphine, codeine, and hydromorphone and more flexible drugs with opiate-like activity such as fentanyl and meperidine to add to a data base which includes experimental electron distributions of naloxone, morphine, and methadone. The long-term objective is to develop the x-ray measurement of electron density distributions and molecular electrostatic potentials into a tool of general utility for the study of drug- receptor interactions.